Notch pathway inhibition mediated by arsenic trioxide depletes tumor initiating cells in small cell lung cancer.

Background: Small cell lung cancer (SCLC) is the most malignant type of lung cancer. We previously reported that arsenic trioxide (As₂O₃) inhibited tumor initiating cells (TICs) of SCLC in vitro. In the present study, we aimed to identify the above effect in vivo and shed light on its underlying mechanism. Methods and results: TICs were enriched by culturing human SCLC cell line as sphere cells in specified serum-free medium. The expression of stem cell markers, CD133 and CD44, and the in vivo tumorigenicity of both TICs and their parental cells were examined. To demonstrate the inhibitory effect of As₂O₃ on TICs, cell proliferation, clone formation and sphere formation assays were performed. CD133 and Notch pathway-related factors were also measured after As₂O₃ treatment. Xenograft models were established by injecting TICs into nude mice. Mice were treated with As₂O₃ for 14 days. Afterwards, the tumor volume and the expression of CD133 and Notch1 were evaluated. TICs obtained by the above-mentioned method showed elevated levels of stem cell markers and increased tumorigenicity compared with their parental cells. As₂O₃ treatment largely inhibited TICs proliferation, sphere formation and clonogenic capacity. As₂O₃ also reduced the expression of CD133 and down-regulated Notch pathway in TICs. Furthermore, As₂O₃ potently inhibited tumor growth, decreased the expression of CD133 and down-regulated Notch1 in tumors originating from TICs. Conclusions: Our data demonstrate that As₂O₃ has a remarkable inhibitory effect on TICs of SCLC both in vitro and in vivo, and the mechanism might involve the down-regulation of Notch pathway. [ABSTRACT FROM AUTHOR]